Purpose::
For autosomal dominant RP (ADRP) 17 disease loci have been mappedthat account for 53.5% of all ADRP cases. Here, we describethe localization and identification of an additional causaldisease gene for an ADRP phenotype in a four-generation Belgianfamily. Subsequent screening of a panel of 87 additional retinaldystrophy families was performed in order to seek extra evidencefor causality.

Results::
A novel ADRP locus of 16.52 cM on 15q21-15qter between D15S153and D15S205 was identified. Refinement of the locus and candidategene analysis led to the identification of a novel mutationc.356G>A (p.G56R) in exon 2 of the NR2E3 gene (MIM 604485),encoding the photoreceptor cell specific orphan nuclear receptorPNR, a key transcriptional regulator that controls photoreceptordifferentiation and maintenance. Screening of the NR2E3 genein other families with similar retinal phenotypes, identifiedthis mutation in two additional families with ADRP. Haplotypeanalysis did not reveal a founder effect, and is thus suggestiveof a mutation hotspot. These findings were obtained prior tothe report of, and completely independently from the data reportedin an ARVO2006 abstract (1033/B966) by L. Bouayed-Tiab and co-workers.In addition, a second novel mutation c.378C>A (p.A63D) wasfound in exon 2 of NR2E3 in a family with cone-rod dystrophy(CRD). Both missense mutations are located in the first zinc-fingerof the DNA-binding domain (DBD) of NR2E3. Mutations in NR2E3have previously been shown to cause autosomal recessive enhancedS-cone syndrome (ESCS), a distinct retinal phenotype.

Conclusions::
Mutations in the first zinc-finger of the DBD of NR2E3 can causeADRP or CRD. It is proposed that a different pathogenetic mechanismunderlying the distinct dominant and recessive phenotypes maybe attributed to the dual role of NR2E3 in the regulation ofphotoreceptor-specific genes. The findings further confirm thepathogenetic parallel between NR2E3 and NRL. Mutations in thelatter can either lead to dominant or recessive phenotypes withstriking similarity to either ESCS or the ADRP reported here.